This invention relates to novel N-hydroxyurea derivatives. The compounds of the present invention inhibit the action of lipoxygenase enzyme, and are useful in the treatment or allevation of inflammatory diseases, allergy and cardiovascular diseases in mammals. This invention also relates to pharmaceutical compositions comprising such compounds.
Arachidonic acid is known to be the biological precursor of several groups of endogenous metabolites, prostaglandins including prostacyclins, thromboxanes and leukotrienes. The first step of the arachidonic acid metabolism is the release of arachidonic acid and related unsaturated fatty acids from membrane phospholipids, via the action of phospholipase. Free fatty acids are then metabolized either by cylooxgenase to produce the prostaglandins and thromboxanes or by lipoxygenase to generate hydroperoxy fatty acids which may be further converted to the leukotrienes. Leukotrienes have been implicated in the pathophysiology of inflammatory diseases, including rheumatoid arthritis, gout, asthma, ischemia reperfusion injury, psoriasis and inflammatory bowel disease. Any drug that inhibits lipoxygenase is expected to provide significant new therapy for both acute and chronic inflammatory conditions.
Recently, several review articles on lipoxygenase inhibitors have been reported. (see H. Masamune and L. S. Melvin, Sr., Annual Reports in Medicinal Chemistry 24 (1989) pp. 71-80 (Academic), B. J. Fitzsimmons and J. Rokach Leukotrienes and Lipoxygenases (1989) pp. 427-502 (Elsevier).
Compounds having structural features similar to those of the present invention are disclosed in European Patent Publication Nos. 279263 A2, and 196184 A2, in U.S. Pat. No. 4,822,809 and Japanese Patent (Kohyo) 502179/1991.